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The effect of maternal type 2 diabetes on fetal endothelial gene expression and function

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Abstract

Aims

Maternal type 2 diabetes (T2D) can result in adverse pathological outcomes to both the mother and fetus. The present study aimed to investigate the pathological effects of maternal T2D on the gene expression patterns and functions of fetal human umbilical vein endothelial cells (HUVECs), a representative of fetal vascular cells.

Methods

Cell proliferation, apoptosis, mitochondrial ROS production and cell cycle were measured using flowcytometry. Genome-wide expression was measured using Affymetrix microarray. Gene expression of CCND2, STAT1, ITGB8, ALDH2, and ADAMTS5 was measured using real-time PCR.

Results

HUVECs derived from T2D mothers (T2D-HUVECs) showed elevated levels of mitochondrial superoxide anions, reduced cell proliferation, and increased apoptosis rates relative to HUVECs derived from healthy control mothers (C.HUVECs). In addition , T2D-HUVECs showed a decreased proportion of cells in G0/G1 and cell cycle arrest at the S phases relative to controls. Interestingly, microarray experiments revealed significant differences in genome-wide expression profiles between T2D-HUVECs and C.HUVECs. In particular, the analysis identified 90 upregulated genes and 42 downregulated genes. The upregulated genes CCND2, STAT1, ITGB8, ALDH2, and ADAMTS5 were validated as potential biomarkers for fetal endothelial dysfunction. Functional network analysis revealed that these genes are the important players that participate in the pathogenesis of endothelial dysfunction, which in turn influences the inflammatory response, cellular movement, and cardiovascular system development and function.

Conclusion

Sustained alterations in the overall function of T2D-HUVEC and gene expression profiles provided insights into the role of maternal T2D on the pathophysiology of the fetal endothelial dysfunction.

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Abbreviations

MMPs:

ADAMTS are zinc metalloproteases

AGE:

Advanced glycation end products

ECs:

Endothelial cells

ET-1:

Endothelin 1

ECM:

Extracellular matrix

GDM:

Gestational diabetes mellitus

C.HUVEC:

Healthy control cells

T2D-HUVECs:

HUVECs derived from T2D mothers

T2D:

Type 2 diabetes

NO:

Nitric oxide

PKC:

Protein kinase C

PI:

Propidium iodide

ROS:

Reactive oxygen species

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Acknowledgements

The author is grateful for mothers who donated cords and nurses who helped with sample collection in Gynecology and Obstetrics department at King Abdulaziz University Hospital. This work was supported by a grant from King Abdulaziz City for Science and Technology (KACST) Grant no 35-180. The author is also grateful to Dr. H. Schulten, Dr. S. Karim, Dr. F, Ahmed and staff from microarray and Bioinformatics unit at the Center of Excellence in Genomic Medicine Research (CEGMR) for their help and technical assistance.

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  1. Medical Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

    Samar Sultan

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Approval of the study was given by the Ethics Committee of the King Abdulaziz University Hospital, Jeddah, Saudi Arabia.

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Informed consent was obtained from all individual participants included in the study.

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Sultan, S. The effect of maternal type 2 diabetes on fetal endothelial gene expression and function. Acta Diabetol 56, 73–85 (2019). https://doi.org/10.1007/s00592-018-1207-y

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